EP0355794A2 - Antagonistes du neuropeptide Y - Google Patents
Antagonistes du neuropeptide Y Download PDFInfo
- Publication number
- EP0355794A2 EP0355794A2 EP89115470A EP89115470A EP0355794A2 EP 0355794 A2 EP0355794 A2 EP 0355794A2 EP 89115470 A EP89115470 A EP 89115470A EP 89115470 A EP89115470 A EP 89115470A EP 0355794 A2 EP0355794 A2 EP 0355794A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- peptide
- pharmaceutically acceptable
- acceptable salt
- preparation
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 102100038803 Somatotropin Human genes 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
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- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
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- 125000001246 bromo group Chemical group Br* 0.000 description 1
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- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
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- 150000001718 carbodiimides Chemical class 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
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- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 235000018417 cysteine Nutrition 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
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- CTAPFRYPJLPFDF-UHFFFAOYSA-O hydron;1,2-oxazole Chemical class C=1C=[NH+]OC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-O 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 150000003932 ketenimines Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 229920000260 silastic Polymers 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical group C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57545—Neuropeptide Y
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to novel peptide derivatives which are antagonists of neuropeptide Y.
- Porcine neuropeptide Y is a 36 amino acid residue peptide that belongs to a unique family of peptides having a wide distribution through- tout the central and peripheral nervous systems. Receptors for NPY are found in the central nervous system and in the periphery. In the brain, NPY is a potent stimulator of food intake, stimulates leutinizing hormone, growth hormone and prolactin, and produces cardiovascular depression. NPY is also a potent peripheral vasoconstrictor and has been reported to cause transient myocardial ischaemia is patients with angina pectoris.
- NPY neuropeptide Y
- Antagonism of these effects is expected to result in reduced blood pressure and accordingly antagonists of NPY are expected to be useful in the treatment of hypertension, vasospasm, and angina, and useful for the suppression of appetite.
- NPY has been shown to be a potent bronchoconstrictor and has been implicated in the regulation of the resting tome of airways.
- NPY antagonists would block the NPY induced constriction and result in bronchodilation.
- Novel peptide derivatives of formula 1 Y-P-S- wherein
- alkyl group is taken to include straight, branched, or cyclic alkyl groups, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, sec-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl and cyclopentylmethyl.
- acyl group of from 2 to 10 carbon atoms is taken to include straight, branched, cyclic, saturated and unsaturated acyl groups having 1 or 2 carbonyl moieties per group, for example, acetyl, benzoyl succinyl, maleyl, and glutaryl.
- Those peptides wherein the amino group of the amino terminal amino acid is substituted with two alkyl or acyl groups are also considered to be within the scope of the peptides of this invention.
- optically active amino acids are of the L-configuration.
- the polypeptides of formula 1 can form pharmaceutically acceptable salts with any non-toxic, organic or inorganic acid.
- inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
- organic acids which form suitable salts include the mono, di and tricarboxylic acids.
- Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
- Salts of the carboxy terminal amino acid moiety include the non-toxic carboxylic acid salts formed with any suitable inorganic or organic bases.
- these salts include those of alkali metals, as for example, sodium and potassium; alkaline earth metals, such as calcium and magnesium; light metals of Group IIIA including aluminum; and organic primary, secondary and tertiary amines, as for example, trialkylamines, including triethylamine, procaine, dibenzylamine, 1-ethenamine, N,N'-dibenzylethylenediamine, dihydroabietylamine, N-(Iower)-alkylpiperidine, and any other suitable amine.
- alkali metals as for example, sodium and potassium
- alkaline earth metals such as calcium and magnesium
- organic primary, secondary and tertiary amines as for example, trialkylamines, including triethylamine, procaine, dibenzylamine, 1-ethenamine, N,N'-dibenzylethylenediamine, dihydroabietylamine, N-(Iower
- the most preferred peptide derivative of formula 1 is the peptide derivative of formula 2.
- the proteins of this invention can be prepared by a variety of procedures readily known to those skilled in the art. Such procedures include the solid phase sequential procedure which can be performed using established automated methods such as by use of an automated peptide sythesizer.
- the resin support employed can be any suitable resin conventionally employed in the art for the solid phase preparation of polypeptides, preferably polystyrene which has been cross-linked with from 0.5 to about 3 percent divinyl benzene, which has been either converted to the p-methylbenz- hydrylamine or benzhydrylamine derivative (for C-terminal amides) orchloromethylated or hydrox- ymethylated to provide sites for ester formation with the initially introduced a-amino protected amino acid (for producing C-terminal alkylamides) and esters.
- polystyrene which has been cross-linked with from 0.5 to about 3 percent divinyl benzene, which has been either converted to the p-methylbenz- hydrylamine or benzhydrylamine derivative (for C-terminal amides) orchloromethylated or hydrox- ymethylated to provide sites for ester formation with the initially introduced a-amino protected amino acid (for producing C-terminal alkylamide
- a tert-butyloxycarbonyl (Boc) protected Thr bound to a benzylated, hydrox- ymethylated phenylacetamidomethyl (PAM) resin can be used and is commercially available.
- the protecting group is removed using any suitable procedure such as by using trifluoroacetic acid in methylene chloride, trifluoroacetic acid alone, or HCI in dioxane.
- the deprotection is carried out at a temperature of between 0 C and room temperature.
- Other standard cleaving reagents and conditions for removal of specific a-amino protecting groups may be used.
- the other amino protected amino acids are coupled step-wise in the desired order.
- multiple amino acid groups may be coupled by the solution method prior to coupling with the resin supported amino acid sequence.
- the a-amino protecting group employed with each amino acid introduced into the polypeptide sequence may be any such protecting group known to the art.
- acyl type protecting groups such as: formyl, trifluoroacetyl, phthalyl, toluenesulfonyl (tosyl), benzenesulfonyl, nitro-phenylsulfenyl, tritylsulfenyl, o-nitrophenox- yacetyl and a-chlorobutyryl;
- aromatic urethan type protecting groups such as benzyloxycarbonyl and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyl- carbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 1-(p-biphenyl-yl)-1
- a particularly suitable coupling reagent where the amino acid to be added is Gin, Asn or Arg is N,N'-diisopropylcarbodiimide and 1-hydroxybenzotriazole. The use of these reagents prevents nitrile and lactam formation.
- coupling agents are (1) carbodiimides (e.g., N,N'-dicyclohexylcarbodiimide and N-ethyl-N'-( ⁇ -dimethylaminopropylcarbodiimide); (2) cyanamides (e.g., N,N-dibenzylcyanamide); (3) ketenimines; (4) isoxazolium salts (e.g., N-ethyl-5-phenylisoxazolium-3'-sulfonate; (5) monocyclic nitrogen containing heterocyclic amides of aromatic character containing one through four nitrogens in the ring such as imidazolides, pyrazolides, and 1,2,4-triazolides.
- carbodiimides e.g., N,N'-dicyclohexylcarbodiimide and N-ethyl-N'-( ⁇ -dimethylaminopropylcarbodiimide
- cyanamides e.g
- heterocyclic amides that are useful include N,N -carbonyldiimidazole and N,N-carbonyl-di-1,2,4-triazole; (6) alkoxylated acetylene (e.g., ethoxy acetylene); (7) reagents which form a mixed anhydride with the carboxyl moiety of the amino acid (e.g., ethylchloroformate and isobutylchloroformate) or the symmetrical anhydride of the amino acid to be coupled (e.g., (Boc-Ala)2-O) and (8) nitrogen containing heterocyclic compounds having, a hydroxy group on one ring nitrogen (e.g., N-hydroxyphthalimide, N-hydroxysuccinimide and 1-hydroxybenzotriazole).
- alkoxylated acetylene e.g., ethoxy acetylene
- Each protected amino acid or amino acid sequence is introduced into the solid phase reactor in about a four-fold excess and the coupling is carried out in a medium of dimethylformamide: methylene chloride (1:1) or in dimethylformamide alone or preferably methylene chloride alone.
- the coupling procedure is repeated before removal of the a-amino protecting group, prior to the coupling of the next amino acid in the solid phase reactor.
- the success of the coupling reaction at each stage of the synthesis is monitored by the ninhydrin reaction as described by E. Kaiser et al, Analyt. Biochem. 34, 595 (1970).
- the peptide is removed from the resin. This can be done by hydrolysis such as by treatment of the resin bound polypeptide with a solution of dimethyl sulfide, p-cresol and thiocresol in liquid hydrofluoric acid.
- suitable side chain protecting groups for lysine are benzyloxycarbonyl and substituted benzyloxycarbonyl, said substituent being selected from halo (e.g., chloro, bromo, fluoro) and nitro (e.g., 2-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 3,4-dichlorobenzyloxycarbonyl), tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl and diisopropylmethoxycarbonyl.
- halo e.g., chloro, bromo, fluoro
- nitro e.g., 2-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 3,4-dichlorobenzyloxycarbonyl
- tosyl t-amyloxycarbonyl, t-butyloxycarbonyl and diisopropylmethoxycarbonyl
- the alcoholic hydroxyl group of threonine and serine can be protected with an acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6-dichlorobenzyl or benzyloxycarbonyl group.
- the carboxylic group of Aspartic acid and Glutamic acid can be protected with a benzyl or cyclohexyl group.
- the preferred protecting group is benzyl.
- protecting groups can be removed by procedures well known in the art. Typically protecting group removal is done after the peptide chain synthesis is complete but the protecting groups can be removed at any other appropriate time.
- peptide derivatives of formula 1 to act as antagonists of neuropeptide Y can be demonstrated by the ability of such peptides to compete with iodinated neuropeptide Y for receptors using the method of Lundberg et al. Eur. J. Pcol. 145:21-9 (1988). 125 I-Bolton-Hunter-neuropeptide Y (BHNPY; Amersham) binding was carried out in pig spleen crude membranes. Membranes from frozen spleen were prepared as described previously for tachykinin peptide binding studies (Buck et al., 1984).
- BHNPY was included in a concentration of 0.1 nM and nonspecific binding was determined by the inclusion of 1 nM pNPY.
- IC 50 values for test peptides were calculated from 6 to 10 point competition curves. Utilizing this procedure the peptide derivative of Example 1 was found to have an IC 50 of ⁇ 300nM.
- the compounds possess valuable pharmacologic properties such as hypotensive, vasospasm, vasodilating and antihypertensive activity as well as depression of food intake desire and depression of leutinizing hormone secretion.
- Significant medical uses of the NPY antagonists of this invention are as antihypertensive agents, antian- ginal agents, antivasospasmotics, and as appetite depressants.
- the dose of a peptide derivative of this invention required to antagonize neuropeptide Y and therefore produce a hypotensive, antihypertensive, vasodilator or other pharmacological or medical effect is from 0.2 mg/kg to 250 mg/kg of patient body weight per day depending on the patient, the severity of the thrombotic condition to be treated and the peptide derivative selected.
- the suitable dose for a particular patient can be readily determined.
- Preferably from 1 to 4 daily doses would be administered typically with from 5 mg to 100 mg of active compound per dose.
- hypotensive, antihypertensive, and vasodilator therapy is indicated for the treatment and prevention of a variety of conditions, particularly coronary artery and cerebrovascular disease such as hypertension and angina. Those experienced in this field are readily aware of the circumstances requiring such therapy.
- patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice.
- non-oral administration for example, subcutaneous, intravenous, intramuscular or intraperitoneal; administration by depot injection; by implant preparation; or by application to the mucous membranes, such as, that of the nose, throat and bronchial tubes, for example, in an aerosol can containing a peptide derivative of this invention in a spray or dry powder form.
- the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
- a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
- oils which can be employed in these preparations are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil.
- water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
- the compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
- the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
- Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber manufactured by the Dow-Corning Corporation.
- the title peptide derivative was synthesized on a 0.5 mmol scale by solid-phase methods on p-methylbenzhydrylamine resin (0.40 mmol/g; Peptides Intl.) using an Applied Biosystems Model 430-A Peptide Synthesizer. All residues were double coupled as the symmetrical anhydrides of the N a t-Boc-protected amino acids with the exception of Arg and Asn which were double coupled by the DCC/HOBT methodology.
- the side chain protection was as follows: Arg(Tos), Asp(Chx), Cys-(pMeBzl), His(Tos), Ser(Bzl), Tyr(2-BrZ) Lys(2-Clz, Thr(Bzl).
- the peptides (0.25 mmol theory) were cleaved from the resin support and deprotected in liquid HF containing 5% anisole at -5 C for 40 min. After removal of the HF in vacuo the peptide was extracted from the resin with 30% acetic acid and water. The extract was diluted to 1 liter, the pH adjusted to between 8 and 9 with ammonium hydroxide and 0.01 N potassium ferricyanide was added until a yellow color persisted (approx. 25 ml). After stirring for 30 min, the pH was lowered to ⁇ 5 with glacial acetic acid and the solution was stirred with 25 ml of settled AG 3-X4A resin (Bio-Rad) for 2 hours. The solution was filtered from the resin and lyophilized.
- the peptidic material that remained was purified by preparative HPLC on a Dynamax C-18 column (41.4 x 250 mm; Rainin) using acetonitrile in 0.1% trifluoroacetic acid as an eluant.
- the purity and identity of the peptide were assessed by analytical HPLC (Vydac 218TP54 column, 4.6 cx 250 mm, 2.0 ml/min, t c - 1.9 min, linear gradient of 15-40% acetonitrile in 0.1% TFA over 25 min), amino acid analysis (AAA) (6 N HCI containing 8% phenol; 106°C; 20 and 40 hr), and fast atom bombardment-mass spectrometry (FAB-MS)-(M-Scan Ltd.).
- AAA amino acid analysis
- FAB-MS fast atom bombardment-mass spectrometry
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AT89115470T ATE100466T1 (de) | 1988-08-26 | 1989-08-22 | Antagonisten von neuropeptid y. |
Applications Claiming Priority (2)
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US23759988A | 1988-08-26 | 1988-08-26 | |
US237599 | 1988-08-26 |
Publications (3)
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EP0355794A2 true EP0355794A2 (fr) | 1990-02-28 |
EP0355794A3 EP0355794A3 (fr) | 1991-01-23 |
EP0355794B1 EP0355794B1 (fr) | 1994-01-19 |
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EP (1) | EP0355794B1 (fr) |
JP (1) | JPH02111793A (fr) |
KR (1) | KR900003203A (fr) |
CN (1) | CN1040594A (fr) |
AT (1) | ATE100466T1 (fr) |
DE (1) | DE68912453T2 (fr) |
DK (1) | DK421489A (fr) |
ES (1) | ES2061839T3 (fr) |
FI (1) | FI894007A (fr) |
HU (1) | HU204541B (fr) |
IL (1) | IL91396A0 (fr) |
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Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993009227A1 (fr) * | 1991-11-06 | 1993-05-13 | Garvan Institute Of Medical Research | Recepteur de neuropeptide y-y1 humain |
WO1994000486A1 (fr) * | 1992-06-20 | 1994-01-06 | The Wellcome Foundation Limited | Antagonistes du neuropeptide y |
EP0838217A2 (fr) | 1996-10-23 | 1998-04-29 | Sanofi | Composition cosmétique contenant un antagoniste des récepteurs du neuropeptide Y |
US5958709A (en) * | 1993-12-28 | 1999-09-28 | Synaptic Pharmaceutical Corporation | Processes for identifying compounds that bind to the human Y4 receptor |
US5989920A (en) * | 1994-12-02 | 1999-11-23 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior compounds useful in such methods and DNA encoding a hypothalmic atypical neuropeptide Y/peptide YY receptor Y5 |
US5989834A (en) * | 1994-02-03 | 1999-11-23 | Synaptic Pharmaceutical Corporation | Uses of nucleic acid encoding neuropeptide Y/peptide YY (Y2) receptors nucleic acid encoding |
US6316203B1 (en) | 1994-12-02 | 2001-11-13 | Synaptic Pharmaceutical Corporation | Methods of screening and preparing a composition using DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
US6713265B1 (en) | 1997-06-04 | 2004-03-30 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior, compounds useful in such methods, and DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
WO2004098591A2 (fr) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Inhibiteurs de glutaminyl-cyclase |
WO2005075436A2 (fr) | 2004-02-05 | 2005-08-18 | Probiodrug Ag | Nouveaux inhibiteurs de la glutaminyl-cyclase |
WO2008055945A1 (fr) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies |
WO2008065141A1 (fr) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Nouveaux inhibiteurs de glutaminylcyclase |
WO2008104580A1 (fr) | 2007-03-01 | 2008-09-04 | Probiodrug Ag | Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase |
WO2009110510A1 (fr) | 2008-03-06 | 2009-09-11 | 萬有製薬株式会社 | Dérivé d'alkylaminopyridine |
WO2011029920A1 (fr) | 2009-09-11 | 2011-03-17 | Probiodrug Ag | Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase |
EP2338490A2 (fr) | 2003-11-03 | 2011-06-29 | Probiodrug AG | Combinaisons utiles pour le traitement de désordres neuronales |
WO2011107530A2 (fr) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2011110613A1 (fr) | 2010-03-10 | 2011-09-15 | Probiodrug Ag | Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011131748A2 (fr) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2012123563A1 (fr) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase |
EP2865670A1 (fr) | 2007-04-18 | 2015-04-29 | Probiodrug AG | Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase |
EP3461819A1 (fr) | 2017-09-29 | 2019-04-03 | Probiodrug AG | Inhibiteurs de la glutaminyl-cyclase |
-
1989
- 1989-08-21 ZA ZA896374A patent/ZA896374B/xx unknown
- 1989-08-22 AT AT89115470T patent/ATE100466T1/de not_active IP Right Cessation
- 1989-08-22 EP EP89115470A patent/EP0355794B1/fr not_active Expired - Lifetime
- 1989-08-22 DE DE89115470T patent/DE68912453T2/de not_active Expired - Fee Related
- 1989-08-22 ES ES89115470T patent/ES2061839T3/es not_active Expired - Lifetime
- 1989-08-22 JP JP1214291A patent/JPH02111793A/ja active Pending
- 1989-08-22 NZ NZ230385A patent/NZ230385A/en unknown
- 1989-08-23 IL IL91396A patent/IL91396A0/xx unknown
- 1989-08-24 PT PT91539A patent/PT91539B/pt not_active IP Right Cessation
- 1989-08-25 FI FI894007A patent/FI894007A/fi not_active Application Discontinuation
- 1989-08-25 KR KR1019890012120A patent/KR900003203A/ko not_active Application Discontinuation
- 1989-08-25 HU HU894418A patent/HU204541B/hu not_active IP Right Cessation
- 1989-08-25 DK DK421489A patent/DK421489A/da not_active Application Discontinuation
- 1989-08-25 CN CN89106526A patent/CN1040594A/zh active Pending
- 1989-08-25 NO NO89893431A patent/NO893431L/no unknown
Non-Patent Citations (1)
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No relevant documents have been found. * |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993009227A1 (fr) * | 1991-11-06 | 1993-05-13 | Garvan Institute Of Medical Research | Recepteur de neuropeptide y-y1 humain |
WO1994000486A1 (fr) * | 1992-06-20 | 1994-01-06 | The Wellcome Foundation Limited | Antagonistes du neuropeptide y |
US5670482A (en) * | 1992-06-20 | 1997-09-23 | Glaxo Wellcome Inc. | Neuropeptide Y antagonists |
US6913892B1 (en) | 1993-12-28 | 2005-07-05 | H. Lundbeck A/S | Method of obtaining compositions comprising Y4 specific compounds |
US5958709A (en) * | 1993-12-28 | 1999-09-28 | Synaptic Pharmaceutical Corporation | Processes for identifying compounds that bind to the human Y4 receptor |
US5976814A (en) * | 1993-12-28 | 1999-11-02 | Synaptic Pharmaceutical Corporation | DNA encoding a human neuropeptide Y/peptide YY/pancreatic polypeptide receptor (Y4) and uses thereof |
US5989834A (en) * | 1994-02-03 | 1999-11-23 | Synaptic Pharmaceutical Corporation | Uses of nucleic acid encoding neuropeptide Y/peptide YY (Y2) receptors nucleic acid encoding |
US6420532B1 (en) | 1994-02-03 | 2002-07-16 | Synaptic Pharmaceutical Corporation | Method of obtaining compositions comprising Y2 specific compounds |
US5989920A (en) * | 1994-12-02 | 1999-11-23 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior compounds useful in such methods and DNA encoding a hypothalmic atypical neuropeptide Y/peptide YY receptor Y5 |
US6316203B1 (en) | 1994-12-02 | 2001-11-13 | Synaptic Pharmaceutical Corporation | Methods of screening and preparing a composition using DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
US6645774B1 (en) | 1994-12-02 | 2003-11-11 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior using compounds with afinity for the human hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
US6818445B2 (en) | 1994-12-02 | 2004-11-16 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior, compounds useful in such methods, and DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
EP0838217A2 (fr) | 1996-10-23 | 1998-04-29 | Sanofi | Composition cosmétique contenant un antagoniste des récepteurs du neuropeptide Y |
US6713265B1 (en) | 1997-06-04 | 2004-03-30 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior, compounds useful in such methods, and DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
WO2004098591A2 (fr) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Inhibiteurs de glutaminyl-cyclase |
EP2338490A2 (fr) | 2003-11-03 | 2011-06-29 | Probiodrug AG | Combinaisons utiles pour le traitement de désordres neuronales |
US7897633B2 (en) | 2004-02-05 | 2011-03-01 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
WO2005075436A2 (fr) | 2004-02-05 | 2005-08-18 | Probiodrug Ag | Nouveaux inhibiteurs de la glutaminyl-cyclase |
WO2008055945A1 (fr) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies |
WO2008065141A1 (fr) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Nouveaux inhibiteurs de glutaminylcyclase |
EP2481408A2 (fr) | 2007-03-01 | 2012-08-01 | Probiodrug AG | Nouvelle utilisation d'inhibiteurs glutaminyle cyclase |
WO2008104580A1 (fr) | 2007-03-01 | 2008-09-04 | Probiodrug Ag | Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase |
EP2865670A1 (fr) | 2007-04-18 | 2015-04-29 | Probiodrug AG | Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase |
WO2009110510A1 (fr) | 2008-03-06 | 2009-09-11 | 萬有製薬株式会社 | Dérivé d'alkylaminopyridine |
WO2011029920A1 (fr) | 2009-09-11 | 2011-03-17 | Probiodrug Ag | Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase |
WO2011107530A2 (fr) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2011110613A1 (fr) | 2010-03-10 | 2011-09-15 | Probiodrug Ag | Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011131748A2 (fr) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2012123563A1 (fr) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase |
EP3461819A1 (fr) | 2017-09-29 | 2019-04-03 | Probiodrug AG | Inhibiteurs de la glutaminyl-cyclase |
Also Published As
Publication number | Publication date |
---|---|
ES2061839T3 (es) | 1994-12-16 |
DE68912453D1 (de) | 1994-03-03 |
ZA896374B (en) | 1990-05-30 |
DK421489A (da) | 1990-02-27 |
PT91539A (pt) | 1990-03-08 |
PT91539B (pt) | 1995-05-04 |
KR900003203A (ko) | 1990-03-26 |
AU620432B2 (en) | 1992-02-20 |
JPH02111793A (ja) | 1990-04-24 |
HUT50486A (en) | 1990-02-28 |
IL91396A0 (en) | 1990-04-29 |
CN1040594A (zh) | 1990-03-21 |
NO893431D0 (no) | 1989-08-25 |
HU204541B (en) | 1992-01-28 |
DK421489D0 (da) | 1989-08-25 |
NO893431L (no) | 1990-02-27 |
DE68912453T2 (de) | 1994-05-11 |
AU4017689A (en) | 1990-03-01 |
EP0355794A3 (fr) | 1991-01-23 |
FI894007A0 (fi) | 1989-08-25 |
ATE100466T1 (de) | 1994-02-15 |
EP0355794B1 (fr) | 1994-01-19 |
NZ230385A (en) | 1992-04-28 |
FI894007A (fi) | 1990-02-27 |
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